NK cells are well known for the capacity to recognize and lyse virus infected cells. Indeed, host defenses in humans and mice that lack NK cell immunity are quite vulnerable to overwhelming and recurrent Herpes virus infections. In C57BL/6 mice, host anti-murine cytomegalovirus (MCMV) immunity requires NK cell expressed Ly49H activation receptor recognition of its virus encoded m157 ligand on MCMV infected cells. We recently showed that NK cells in NZW mice however, control experimental MCMV infection without a role for Ly49H+ NK cells. Herein we have extended our finding in MA/My mice. The MA/My strain is noteworthy since it also displays very effective NK cell-mediated control of MCMV infection, but NK cells in this strain do not express Ly49H receptors. Interestingly, MCMV resistance in MA/My is strongly associated with MHC and also non MHC genes. Thus, we have found that NK cells utilize multiple antiviral control mechanisms that are distinguished by genetic polymorphism. The long-term objective of this research proposal therefore is to understand how genetic variation in host genes can contribute differently in innate immunity, its capacity to rapidly recognize and destroy viral pathogens at early times after infection and the molecular and cellular mechanisms controlling such host defenses. The Specific Aims herein will focus initially on the identification and characterization of host genes that contribute substantially to innate anti-MCMV immunity through classical Mendelian genetics studies. The approach is based on rapid phenotypic characterization of hybrid offspring after experimental MCMV infection and subsequent genome-wide genotypic identification of each individual. Using this high-throughput genetics strategy, chromosome locations will be identified in quantitative genetics strategies, confirmed in interval-specific congenic strains, and subsequently candidate genes will be assessed in prospective molecular and biochemical analyses. To facilitate identification of host virus resistance genes, we will also investigate NK cell recognition of virus infection in cellular cytotoxicity assays and virus strain variant selection will also be used to understand innate host defenses mechanistically. While NK cells employ multiple defense mechanisms to control viral pathogens immediately after infection and before adaptive immunity is competent, our studies will no doubt have important implications for human innate defenses in CMV and potentially other virus infections.